Chronic heart failure (CHF)-induced cardiac sympathetic overactivity is involved in sudden cardiac death and is responsible for high mortality in patients with CHF. However, the potential mechanisms concerning cardiac sympathetic overactivity in the CHF state are unclear. Cardiac postganglionic sympathetic (CPS) neurons located in stellate ganglia regulate cardiac function by influencing release of norepinephrine (NE) and neuropeptide Y (NPY) from these neuronal terminals innervating the heart. Ca++ influx through voltage-gated Ca++ channels is a key trigger for the release of NE and NPY from these neuronal terminals. Our recent study has shown that N-type Ca++ currents and cell excitability in CPS neurons are enhanced in coronary artery ligation-induced CHF rats, which are accompanied by cardiac sympathetic hyperactivity. Based on our preliminary data, we hypothesize that CHF-mediated inflammation cytokines in CPS neurons evoke N- type Ca++ channel activation via cyclin-dependent kinase (Cdk5) signaling, and N-type Ca++ channel activation then contributes to cardiac sympathetic hyperactivity in CHF. Myocardial infarction-induced CHF and sham (sham surgery) rats and mice will be used as the primary experimental tool in this project. Using multi-faceted technical approaches (from whole-animal to cellular-molecular levels) in sham and CHF rats, we will design in-vitro (cells and tissues) and in-vivo (conscious and anesthetized rats) studies to assess this question. In specific Aim 1, we will measure whether CHF-increased N-type Ca++ currents in CPS neurons contribute to cardiac sympathetic hyperactivity in CHF as measured by cardiac sympathetic nerve activity, in- vivo release of NE and NPY from CPS nerve terminals, and heart rate variability. In Specific Aim 2, we will test whether CHF-increased N-type Ca++ currents in CPS neurons trigger cardiac rhythm instability in CHF. In Specific Aim 3, we will measure whether inflammatory cytokine-Cdk5 signaling pathway modulates N-type Ca++ channels in CPS neurons of CHF rats. These studies will further our understanding of the cellular and molecular mechanisms responsible for the cardiac sympathetic hyperactivity in CHF and will also explore potential therapeutics (N-type Ca++ channel blockers and new anti-inflammatory drugs) for improving cardiac sympathetic function and reducing mortality in the CHF state.